Mantle cell lymphoma (MCL), characterized by a t(11;14) translocation that results in up-regulation of cyclin D1, is incurable with standard chemotherapy. Several new drugs are currently undergoing early clinical testing in MCL. Recent phase II studies have shown that bortezomib (BZM), an inhibitor of the proteasome, can induce responses in about 50% of pre-treated patients (O?Connor et al, JCO 2005, Goy et al, JCO 2005) However, the molecular mechanisms underlying either chemo sensitivity or resistance to BZM in MCL remain largely unknown. Likewise, optimal combination treatment regimens incorporating BZM remain to be defined. The NCI recently initiated a phase II study combining BZM with rituximab and dose adjusted, infusional EPOCH chemotherapy (etoposide, prednisone, vincristine, doxorubicin and cyclophosphamide) in patients with untreated MCL. EPOCH-R has been shown to be a highly active regimen in a previous study inducing CR in 92% of treated patients (Neelapu et al, Nat Med 2005). Patients in the current study are treated with one cycle of BZM single agent, followed by 6 cycles of combination induction therapy. Lymph node biopsies are obtained pre-treatment and after 2 doses of BZM. In patients with the leukemic form of MCL blood samples are analyzed in detail during the single agent treatment period. These blood and lymph node samples are analyzed using gene expression profiling to investigate predictors of treatment response and possible mechanisms of drug resistance.[unreadable] [unreadable] Initial results in our laboratory on patients with leukemic MCL showed that BZM was preferentially cytotoxic to the malignant B cells, as evidenced by stable T-cell counts. In the leukemic cells, BZM affected the expression of hundreds of genes compared to untreated samples. Many genes differentially expressed with the treatment included genes involved in the response to reactive oxygen species and their detoxification. These findings could be confirmed in MCL cell lines. This type of response could help restore cellular homeostasis and protect the cells from apoptosis and could therefore contribute to drug resistance or be a marker of an overwhelming insult before the cells undergo apoptosis. Further studies aim to better characterize this response, define whether it leads to apoptosis or contributes to drug resistance and explore drug combinations that could increase bortezomib induced cell death in tumor cells.